SYSTEMIC AND METABOLIC CONSIDERATION OF NEPHROLITHIASIS Marshall L. Stoller, M.D. Professor and Vice Chairman Department of Urology University of California San Francisco Urinary Calculus Disease Incidence: 7-21/10,000 3 men: 1 woman Peak age of onset: 20-30 years Morbidity > Mortality Urinary Calculus Disease Five major stone types Calcium oxalate Monohydrate / Dihydrate Calcium phosphate Brushite / Apatite Struvite Infection stones Uric acid ph < 5.5 Cystine SLC 3a1 1
Urinary Calculus Disease Struvite Infection stone Magnesium ammonium phosphate ph always > 7.2 Woman much more common than men Urease producing organisms Rarely present with ureteral stones/colic without prior manipulation Urinary Calculus Disease Uric acid ph < 5.5 Radiolucent Men > women Medical dissolution -- increased ph Effective prophylaxis -- increased ph High recurrence rate without medications Urinary Calculus Disease Cystine Ground glass radiographic appearance Smooth edges Frustrating recurrence despite medical therapy Thiola - disulfide binder Urinary alkalinization 2
Urinary Calculus Disease General dietary recommendations Decrease sodium intake Eliminate salt shaker at table Assess sodium when shopping Eating out increases sodium intake Decrease animal protein intake Oral fluid intake adequate to void 1.5 L/day Urinary Calculus Disease Hypercalciuria Hyperuricosuria Hyperoxaluria Hypocitraturia Calcium Nephrolithiasis Hypercalciuria Hyperuricosuria Absorptive Endogenous Resorptive Dietary excess Renal Hypocitraturia Hyperoxaluria Metabolic acidosis Primary Enteric 3
PATIENT HC PAST UROLOGIC HISTORY Left SWL 2001 Left URS with laser lithotripsy 03, 05 No history of metabolic stone workup FAMILY HISTORY Mother with stones (no surgery) Brother with stones s/p SWL PATIENT HC ROS negative PMH diabetes mellitus hypertension obesity angina s/p cardiac stent in 2007 MEDICATIONS glyburide lisinopril HCTZ aspirin 4
PATIENT HC SOCIAL HISTORY married 2 children emigrated from Japan 25 years ago owns local bookstore 20 pack year tobacco history social EtOH sleeps left side down PATIENT HC PE 5 3 tall, 183 lbs BMI = 32.4 BP 146/88, HR 75 Abdomen soft, non-tender, non-distended, healed percutaneous puncture site KUB no residual stones FURTHER WORKUP? 5
TRADITIONAL WORKUP Serum studies Parathyroid hormone Uric acid Calcium Electrolytes, BUN / creatinine 24-hour urinalysis (for recurrent stones) Historical thinking treat abnormalities found on serum and urine studies WHAT HAVE WE LEARNED ABOUT METABOLIC STONE DISEASE IN THE PAST 10 YEARS??? SYSTEMIC DISEASE IS A RISK FACTOR FOR NEPHROLITHIASIS AND (PERHAPS EQUALLY IMPORTANT) NEPHROLITHIASIS IS A RISK FACTOR FOR SYSTEMIC DISEASE 6
RISK FACTORS FOR NEPHROLITHIASIS Hypertension, diabetes mellitus Obesity, metabolic syndrome Gender? Sleep position? History of angina and atherosclerosis? Family history of stones? Race HYPERTENSION Epidemiologic evidence Patients with hypertension are at risk for stones Stone-formers are at risk for hypertension HYPERTENSION If you have hypertension 1 Cappuccio 503 men 8 yr f/u 2 Borghi 260 men 8 yr f/u RR of stones 1.89 (1.12-3.18) RR of stones 5.5 (1.82-16.66) If you have nephrolithiasis 3 Madore 51,529 men > 15 yr f/u 4 Madore 89,376 women > 15 yr f/u RR of HTN 1.29 (1.12-1.41) RR of HTN 1.24 (1.13-1.37) 1 Capuccio (1999), 2 Borghi (1999), 3 Madore (1998), 4 Madore (1998) 7
WHY DO HYPERTENSIVES FORM STONES? Proposed mechanisms hypertensive subjects leak calcium from nephron 1 hypertensive subjects excrete less citrate 2 more uric acid 3 more oxalate 4 increased dietary sodium intake 5,6 1 Strazullo (1995), 2 Taylor (1998), 3 Tisler (2002), 4 Borghi (1999), 5 Muldowney (1982), 6 Androgue (1978) WHY DO STONE-FORMERS BECOME HYPERTENSIVE? Proposed mechanisms nephrolithiasis leads to renal damage obstructive uropathy 1 direct injury to tubular epithelial cells 2 1 Gambaro (2001), 2 Knoll (2004) DIABETES MELLITUS Epidemiologic evidence Women with diabetes mellitus are at risk for stones Stone-formers are at risk for diabetes mellitus 8
DIABETES MELLITUS If you have diabetes, incident stone risk is -Older women 1.29 (1.05-158) -Younger women 1.60 (1.16-2.21) -Men 0.81(0.59-1.09) If you have nephrolithiasis, incident diabetes risk is -Older women 1.33 (1.18-1.50) -Younger women 1.48 (1.14-1.91) -Men 1.49 (1.29-1.72) 1 Taylor (2005) WHY DO DIABETICS FORM STONES? Proposed mechanisms increased uric acid production 1 decreased urine ph impaired renal ammonium production from insulin resistance 2 elevated serum glucose decreased renal calcium reabsorption 3 increased filtered calcium 4 1 Daudon (2006), 2 Taylor (2005), 3 Lemann (1970), 4 Lemann (1969) DIABETES AND 24-HOUR URINE CHEMISTRIES AT UCSF DM DIET ADJUSTED Sodium 20.7 (1.8 39.4) Calcium -15.9 (-46.4 14.6) Citrate 57.9 (-54.7 167.5) Uric acid 0.02 (-0.02 0.1) Oxalate 6.1 (0.9 11.3) Potassium -2.6 (-9.7 4.5) Phosphorus -0.1 (-0.2-0.004) Magnesium -0.03 (-11.0 11.1) Sulfate -0.9 (-4.5 2.6) ph -0.3 (-0.5-0.02) Volume 0.4 (0.1 0.6) SSCaOx 0.02 (-0.9 1.0) SSCaP 0.2 (-0.05 0.4) SSUa -0.03 (-0.2 0.1) Creatinine -74.6 (-153.6 4.4) Eisner, Porten, Bechis, Stoller (unpublished data) Multivariate linear regression 469 stone-forming patients Adjusted for age, gender, race, diet, hypertension, obesity, thiazide and K-Citrate use DIABETES IS ASSOCIATED WITH INCREASED SODIUM OXALATE AND DECREASED URINE ph 9
DOES SWL CAUSE HYPERTENSION AND DIABETES Retrospective questionnaire review SWL versus ureteroscopy 1 Increased HTN and diabetes in SWL group Question: cause or effect? 1 Krambeck (2006) OBESITY Epidemiologic evidence Obesity increases risk of nephrolithiasis Increasing BMI increases risk of nephrolithiasis Weight gain increases risk of nephrolithiasis (but weight loss does not reduce risk) OBESITY Weight and incidence of stones < 150 lbs versus > 220 lbs Older women RR 1.92 (1.59-2.31) Younger women RR 1.89 (1.52-2.36) Men RR 1.44 (1.11-1.86) 1 Taylor (2005) 10
OBESITY BMI and incidence of stones < 21 versus 30 Older women RR 2.09 (1.77-2.48) Younger women RR 1.90 (1.61-2.25) Men RR 1.33 (1.08-1.63) 1 Taylor (2005) OBESITY Weight change and incidence of stones 35 pound weight gain Older women RR 1.82 (1.50-2.21) Younger women RR 1.70 (1.40-2.06) Men RR 1.39 (1.14-1.70) No change in risk with weight loss 1 Taylor (2005) OBESITY AND 24-HOUR URINE CHEMISTRIES BMI 30 associated with lower urine ph hyperuricosuria hypocitraturia 1 Highest quintile of BMI associated with increased urine oxalate Increased urine uric acid Increased urine sodium 1 Ekeruo (2004), 2 Taylor (2006) 11
OBESITY AND 24-HOUR URINE CHEMISTRIES Obese men and women versus their non-obese counterparts increased sodium increased calcium increased oxalate increased uric acid increased citrate decreased ph 1 1 Powell CR, Stoller ML, Schwartz BF, et al. (2000) OBESITY AND 24-HOUR URINE CHEMISTRIES AT UCSF Multivariate analysis of relationship between BMI and urine chemistries, stratified by age and gender 1 Older women increasing urine sodium decreasing urine calcium Younger women increasing urine sodium increasing urine uric acid Older men increasing urine sodium decreasing urine ph Younger men increasing urine sodium increasing urine citrate decreasing urine ph decreasing urine calcium 1 Eisner BH, Eisenberg ML, Stoller ML (submitted, 2009) WHY DO OBESE PATIENTS FORM STONES? Proposed mechanisms Insulin resistance leads to changes in urine chemistries oxalate calcium uric acid ph 1 Powell (2000), 2 Eisner (submitted 2009) 12
OBESITY AND 24-HOUR URINE CHEMISTRIES AT UCSF OB DIET ADJUSTED Sodium 40.1 (26.7 53.4) Calcium -10.5 (-32.8 11.8) Citrate 17.3 (-62.3 97.5) Uric acid 0.05 (0.02 0.09) Oxalate -1.2 (-5.0 2.6) Potassium 0.4 (-4.8-5.6) Phosphorus 0.06 (0.002 0.2) Magnesium -1.87 (-10.0 6.2) Sulfate -3.7 (-6.3-1.1) ph -0.2 (-0.2-0.01) Volume -0.03 (-0.2 0.2) SSCaOx 0.05 (-0.7 0.8) SSCaP -0.01 (-0.2 0.2) SSUa -0.08 (-0.05 0.2) Creatinine 136.8 (78.5 195.1) Eisner, Porten, Bechis, Stoller (unpublished data) Multivariate linear regression 469 stone-forming patients Adjusted for age, gender, race, diet, hypertension, diabetes, thiazide and K-Citrate use OBESITY IS ASSOCIATED WITH INCREASED SODIUM URIC ACID AND DECREASED URINE ph METABOLIC SYNDROME Metabolic syndrome 3 of the following required diabetes mellitus hypertension obesity increased serum triglycerides decreased serum HDL METABOLIC SYNDROME Epidemiologic evidence Patients with metabolic syndrome are at risk for stones Stone-formers are at risk for metabolic syndrome 13
METABOLIC SYNDROME NHANES III - > 13,000 Americans Risk of nephrolithiasis increases with # of metabolic syndrome traits 1 trait RR 1.27 (0.77-2.10) 3 traits RR 1.76 (1.08-2.85) 5 traits RR 1.93 (1.04-3.56) 1 West (2009) METABOLIC SYNDROME 2,132 men and women from S. Italy Patients with hypertension are at increased risk of nephrolithiasis Risk is greater in patients with obesity PLUS hypertension suggesting additive effects 1 1 Redina (2009) METABOLIC SYNDROME CARDIA Study 5,115 Americans, recruited at age 18-30 in 1985-1986, followed for 20 years Multivariate analysis adjusting for age, gender, race, tobacco, and education Nephrolithiasis predicts incidence of metabolic syndrome β = 1.89 (95% CI 1.30-2.78), p=0.001 1 Eisner, Reiner, Jacobs, Kahn, Stoller (unpublished data) 14
FAMILY HISTORY Studies on rare genetic diseases cystinuria SLC3A1, SLC3A9 X-linked nephrolithiasis (Dent s disease) CLCN5 FAMILY HISTORY 1 large study in the literature looking at nephrolithiasis in twins 1 Proband concordance for nephrolithiasis monozygotic (MZ) twins 32% dizygotic (DZ) twins 17% Tetrachoric analysis - Heritability risk for nephrolithiasis 56% 1 Goldfarb (2005) FAMILY HISTORY Hospitalization rates for nephrolithiasis in Danish Twin Study (30,000 twin pairs) Proband concordance Monozygotic twins 13.6% Dizygotic twins 2.2% p <0.001 1 Stoller, Eisner, Kahn, Kristensen (unpublished data) 15
RACE (ASIAN vs. WHITE) Relative Risk (95% CI) Hypercalciuria 1.04 (0.50 2.12) Hyperoxaluria 0.92 (0.50 1.70) Hypocitraturia 2.33 (1.28 4.34) Hyperuricosuria 5.56 (2.57 12.40) Urine Sodium > 150 1.66 (0.85 3.28) Urine ph < 5.8 n/a e SSCaOx > 10 1.12 (0.46 2.67) SSCaP > 2 1.25 (0.44 3.51) SSUA > 1 7.02 (1.23 47.7) 1 Eisner, Porten, Bechis, Stoller (unpublished data) Multivariate logistic regression 462 stone-forming patients Adjusted for age, gender, diet, HTN, diabetes, BMI, thiazide and K-Citrate use ASIAN RACE INCREASES RISK OF HYPOCITRATURIA HYPERURICOSURIA INCREASED URIC ACID SUPERSATURATION (WHITE RACE IS REFERENT) COULD THE VASCULAR SYSTEM BE INVOLVED IN STONE FORMATION??? 16
Alexander Randall Stones related Calcifications beneath papillary epithelium Specifically: calcified basement membrane of collecting ducts 17
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Intimate association between the collecting ducts and the papillary vasa recta Is the primary stone event a vascular or uriniferous phenomenon? Sleep for 6-12 hours / day Normal subjects sleep for prolonged periods in lateral decubitus position Younger patients move less POSTURE AND MAG-3 RENAL PERFUSION Left Side Right Side Supine 51.9% 48.1% Left side down 61.3% 38.7% Right side down 36.7% 63.3% 19
Is the initiating stone event vascular in origin? Electron microscopy shows that cells of renal papilla, where stones are often attached are associated with capillaries Biopsy of Randall s plaques shows crystal deposits in vasa rectae of renal papilla If the initial stone event is vascular in origin, then stone formers should be at increased risk for developing other systemic vascular conditions. Health Professionals Follow-up Study (HPFS) Prospective study of ~50,000 MEN Determine whether nephrolithiasis is an independent risk factor for vascular disease 20
20 year follow-up biennial questionnaires Multivariate analysis comparing risk of incident myocardial infarction coronary surgery or revascularization in men +/- a history of nephrolithiasis No Nephrolithiasis nephrolithiasis Person years 561,404 64,575 Myocardial infarction Number of cases 1712 258 Multivariable RR 1.00 (ref) 1.16 (1.02-1.33) Coronary artery bypass graft 2845 448 Number of cases 1.00 (ref) 1.16 (1.05-1.28) Multivariable RR Total Coronary Heart Disease 4114 633 Number of Cases 1.00 (ref) 1.15 (1.06-1.26) Multivariable RR NEPHROLITHIASIS IN MEN IS ASSOCIATED WITH INCREASED RISK OF MYOCARDIAL INFARCTION CORONARY REVASCULARIZATION Eisner, Cooperberg, Curhan, Stoller (2007) Study of Osteoporotic Fractures (SOF) Prospective study of ~10,000 WOMEN Determine whether nephrolithiasis is an independent risk factor for vascular disease 21
Baseline medical questionnaires Multivariate analysis comparing risk of prevalent Myocardial infarction Angina Congestive heart failure Cardiovascular mortality in women +/-a history of nephrolithiasis Myocardial infarction Number of cases Multivariable RR Angina Number of cases Multivariable RR Congestive heart failure Number of cases Multivariable RR No Nephrolithiasis nephrolithiasis 9054 (95.6%) 426 (4.6%) 507 48 1.00 (ref) 1.78 (1.21-2.62) 895 67 1.00 (ref) 1.61 (1.18-2.23) 211 21 1.00 (ref) 2.23 (1.30-3.84) NEPHROLITHIASIS IN WOMEN IS ASSOCIATED WITH INCREASED PREVALENT MYOCARDIAL INFARCTION ANGINA CONGESTIVE HEART FAILURE BUT NOT MORTALITY Eisner, Stone, Cooperberg, Kahn, Stoller (2009) NEPHROLITHIASIS AND CORONARY ARTERY CALCIUM CARDIA Study 5,115 Americans, recruited at age 18-30 in 1985-1986, followed for 20 years Linear regression model Nephrolithiasis is associated with increasing CAC (Coronary Artery Calcification) score β = 1.77 (95% CI 1.20-2.60), p=0.004 Eisner, Reiner, Jacobs, Kahn, Stoller (unpublished data) 22
NEPHROLITHIASIS AND CAROTID ARTERY THICKNESS Multivariate model adjusting for age, gender, race, tobacco use, DM, BMI Nephrolithiasis is associated with increasing carotid artery wall thickness β = 0.136 (95% CI 0.012-0.26), p=0.03 1 Eisner, Reiner, Jacobs, Kahn, Stoller (unpublished data) NEPHROLITHIASIS CORONARY ARTERY CALCIUM CAROTID ARTERY THICKNESS NEPHROLITHIASIS IS ASSOCIATED WITH INCREASED CORONARY ARTERY CALCIUM INCREASED CAROTID ARTERY WALL THICKNESS TAKE HOME MESSAGES Etiology of nephrolithiasis is incompletely understood Traditional theories of abnormal urine chemistries do not fully explain stone disease Need to get beyond the 24-hour urine to fully understand patients with nephrolithiasis 23
TAKE HOME MESSAGES Recent evidence linking nephrolithiasis to systemic disease (hypertension, diabetes, obesity) New research shows accumulating epidemiologic and anatomic evidence for vascular etiology of urinary stones May have an impact on future therapy A STONE IS A STONE IS A STONE OR MAYBE IT ISN T!!! 24
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